In modern surgery, wide use is made of implants, namely, the introduction into the body of materials that can replace damaged parts of the same; in particular, implants are very common for replacing bones or sections thereof, or for temporarily fill voids in the bone structure, that are to be afterwards replenished by the growth of fresh bone tissue. Examples of these surgery areas are the maxillofacial surgery, in which damaged parts of the face are reconstructed; dentistry, in which the implants are mainly directed to create a stable seat in the maxillar or mandibular bone for metal elements to which prostheses will then be fixed; aesthetic surgery, in which implants are mostly directed to fill wrinkles; and orthopedic surgery, in which the insertion of material into the damaged part has generally the function of providing a temporary substitute for natural tissues and a suitable substrate for their re-growth during the healing process (and possibly also a promoting effect for such re-growth).
In orthopedic surgery, a particularly challenging application is the treatment of articular lesions, because of the need of preserving the mobility of the part (which may be not an issue in other surgery areas), and because in many cases the damage to be repaired involves both bone and cartilage tissues.
The description that follows will refer mainly to orthopedic surgery, but the biomaterials described below are of general application, at least in the other surgery areas mentioned before.
Osteochondral lesions, i.e., affecting both the bone and the cartilage connected thereto, are the most serious ones in the typical classifications of cartilage defects; in the classification of defects according to Outerbridge, the osteochondral defect represents level IV, which is the maximum level in terms of severity of the lesion. These lesions were formerly treated only with the implant of metal prostheses, but more recently implant materials which are more similar to the tissues to be repaired or regenerated have been used, which have better expectations of success in the long run; in fact, especially in the case of younger patients, obtaining the regeneration of a new bone and cartilage tissue in the area of the lesion in a joint allows the affected patient to regain the original form of the joint, i.e. of perfect efficiency, and above all a repair tissue which is fully integrated with the circulatory system, the lymphatic system, and even with the nervous system. To this end, materials have been developed which form the so-called “scaffolds”, i.e., supports having a three-dimensional structure on which the patient's repairing cells cling and migrate during the process of rehabilitating the space left by the osteochondral damage.
Products have long been known and used, which consist of or contain hydroxyapatite (Ca5(PO4)3OH) and/or the crystalline form β of tricalcium phosphate (Ca3(PO4)2), for the preparation of scaffolds useful for the bone tissue regeneration.
Hydroxyapatite (often referred to by the abbreviation HA in the field, which will be used hereafter) is a material with a high biomimetic attitude against the bone tissue, with a porosity very similar to that of the spongy tissue of the bone and capable of accommodating osteoblasts, thus allowing them to settle and transform into osteocytes; moreover, it has excellent biocompatibility, and when placed in direct contact with the bone it shows osteoconduction and osteointegration and, in the presence of bone growth induction factors, also osteoinduction. Moreover, this material is the main mineral constituent of the bones, being 60% of the calcified human skeleton, and is therefore a natural candidate for the production of bone prostheses or fillers. It has been produced synthetically since the 70s, using a sintering process (agglomeration of a powder at a temperature below its melting point), and has been used clinically for about 20 years. However, HA has a poor degradability by body fluids and is therefore resistant to in vivo absorption.
For the production of scaffolds for bone regrowth, HA is therefore used in a mixture with a second mineral component, the crystalline form β of tricalcium phosphate (Ca3(PO4)2), commonly known as β-tricalcium phosphate or by its abbreviation β-TCP, which will be used hereafter. β-TCP has a faster resorption than HA, and therefore promotes the regrowth of the bone tissue. These mixtures, referred to in the field by the abbreviation HA/β-TCP, may have different ratios of the two components.
A variety of biocompatible and biodegradable materials consisting of HA/β-TCP for use in orthopedic surgery is known.
The product OpteMx® by Exactech (Gainesville, Fla., USA) is available as preformed parts (e.g. parallelepiped or cylindrical in shape) consisting of the porous HA/β-TCP composition only, and has osteogenesis and limited osteoinduction properties when mixed with bone marrow blood.
The product MasterGraft® by Medtronic (Minneapolis, Minn., USA), available in granules of the HA/β-TCP composition only, has osteoconduction properties.
However, these materials are very fragile and thus not flexible, and poorly suitable for use in case of bone lumens or surfaces which are irregular in shape.
In order to overcome the problem, HA/β-TCP mixtures can be filled into a flexible matrix; the matrix material must be such that the final composite retains biocompatibility features. Widely used to this purpose is collagen, the most important structural protein in the human body, forming molecular wires which strengthen the tendons and large, elastic sheets that support the skin and internal organs. Bones and teeth are made of mineral crystals added to collagen. Collagen is a relatively simple protein, consisting of three chains, each containing more than 1400 aminoacids, wrapped together in a triple narrow helix.
Several products are known on the market which consist of HA and/or β-TCP in a collagen matrix.
The product MasterGraft® Putty by Medtronic, having osteoconduction properties, is formed by the same granules as the product MasterGraft® mentioned above, evenly distributed in a bovine collagen matrix.
The product Integra Mozaik™ by Integra LifeSciences Corporation (Plainsboro, N.J., USA), with osteoconductive properties, consists of a mixture containing about 80% β-TCP and 20% collagen.
The product Collagraft® Bone Graft Matrix by Zimmer (Warsaw, Ind., USA) is sold in the form of strips made of HA/β-TCP in a collagen matrix, which when added to autogenic bone marrow blood promote the bone repair process.
Finally, the product Healos® by DePuy (Warsaw, Ind., USA) consists of a matrix of cross-linked collagen fibers coated with HA; this product, combined with marrow blood, offers an excellent environment for the proliferation and differentiation of osteoprogenitor cells.
In cases of lesions affecting both the bone and the cartilage, the healing of the cartilage lesion is promoted by collagen, while that of the bone by the mineral components; known products, wherein HA and/or β-TCP are evenly distributed in the collagen matrix, are not optimal for these complex lesions.
Patent application WO 2011/064724 A1 describes mono-, bi- or multi-layer biomimetic materials for use in orthopedic surgery, and the process for their production. The basic material described in this application is a bicomponent material made of the natural polymer collagen added with chitosan (a polymer obtained by basic deacetylation of chitin, the natural component of exoskeleton of crustaceans). The mono-layer biomimetic materials of this application are made of collagen-chitosan only. This bicomponent material contains between 30 and 90% (preferably 50-80%) by weight of collagen, the remainder being chitosan; the role of chitosan is said to be for favoring the fibration of the bicomponent material. The production process of this collagen-chitosan material is however rather complex, requiring a rather complex sequence of steps carried out at controlled and different pH values. This application also describes a double layer material, comprising a layer of the collagen-chitosan material only, and a second layer of the same polymers containing nano- or microdimensional crystals or granules of HA (the preferred size of these crystals or granules being between 30 nm and 10 μm). A double layer material is said to be useful for the healing of osteochondral lesions, and is used by contacting the polymers-only layer with the lesion area in the cartilage, and the layer containing HA with the lesion area in the bone tissue. These double layers are obtained by preparing the collagen-chitosan material according to the same complex process mentioned above, and in particular preparing a layer made of polymers only, a separate layer made of polymers loaded with the nano- or micro-crystals or granules of HA, and then joining the two layers separately produced. The double layer materials of this application, though more suitable for the treatment of osteochondral lesions than polymeric materials in which HA is uniformly distributed, are of cumbersome preparation, due to the complexity of the preparation of the bicomponent polymeric material, and the need of producing the two layers separately.
It is the object of the invention to overcome the problems still existing in the field, and in particular to provide a composite useful as a matrix for the regeneration of tissues in several areas of surgery, and in particular in orthopedic surgery for the treatment of lesions affecting both the bone tissue and the cartilaginous tissue at the same time.